ABSTRACT It is fundamentally important to understand how functional information is encoded by a genome. Characterizing these functional elements can bring novel mechanistic insights into biological processes ranging from normal development to disease progression. I developed a computational algorithm to analyze ribosome profiling data, and unexpectedly revealed thousands of short open reading frames (sORFs) encoded by putative ?noncoding? regions, including lncRNAs, pseudogenes, and 5?UTRs. Some of the sORFs are conserved across species, suggesting biological importance. My results together with several other genetic studies in model species have opened up a research frontier to study the biological roles of sORFs encoded in a genome. Here I propose to use integrated computational and experimental genomics approaches to systematically characterize biological functions of sORFs. First, we will study basic principles driving sORF conservation and expression across eukaryotes. Second, we will study the stability and degradation pathways of sORF-encoded micropeptides. Third, we will examine the importance of sORFs for regulating cell proliferation. Finally, we will study the functional roles of sORF translation in regulating RNA stability. Taken together, our study will shed light on the functional characterization of the newly identified translated regions in a genome and provide novel insights into the interplay between RNA translation and genome evolution. Our findings will have far-reaching implications for the molecular understanding of translational control and peptide functions underlying development and diseases.